LAUSR

The pathophysiological basis of hypomania/mania and its link with immune dysregulation has been sparsely investigated and is poorly understood. Magioncalda et al. (2018) narrow this gap by quantifying white matter (WM) pathology together with the frequencies of circulating T-cell subpopulations in a well-characterized sample of 60 participants with Type I Bipolar Disorder (BD) – 20 participants in the manic phase, 20 participants in the depressed phase, and 20 participants who were euthymic at the time of the study. A further 20 healthy participants served as comparison controls (HCs). There were three main findings: Firstly, the diffusion tensor imaging (DTI)-derived measures of WM pathology (altered fractional anisotropy and radial diffusivity) were most salient in the acute phase of illness, particularly in the manic group, with the decrease in integrity of WM tracts concentrated in midlines structures such as the corpus callosum and corona radiata. Secondly, relative to HCs, the participants with mania displayed an increase in plasma IL-6 and circulating CD4+ cells together with a decrease in circulating CD8+ cells. The increase in the CD4+ population was driven by an increase in naïve and central memory subsets while the decrease in the CD8+ population was underpinned by a decrease in effector memory, terminal effector memory, and IFNγ-producing (functionally active) cellular subtypes. Thirdly, in the mania sample, reduced WM integrity in the corpus callosum and left superior corona radiata was associated with the decrease in terminal effector memory and IFNγ+ CD8+ populations. Central memory cells maintain long-lived T-cell memory and are capable of homing to secondary lymphoid tissues. In contrast, effector memory cells are highly differentiated memory T cells which are capable of immediate inflammatory cytokine production and cytotoxicity. Partly because IL-6 levels were inversely correlated with CD8+ terminal effector memory cells, which are prone to tissue migration, the authors interpret the decrease in peripheral CD8+ populations to be a consequence of chronic immune activation in mania. Thus, the authors postulate that the putative extravasion of active CD8+ cells reflects a Tcell-mediated pathogenic process in the brain parenchyma that leads to WM abnormalities in BD. In support of the authors’ hypothesis, a link between WM pathology and CD8+ cell activation has been reported in other inflammatory illnesses such as multiple sclerosis (Baecher-Allan et al., 2018). It is noteworthy that reductions in the numbers or density of oligodendrocyte cells are one of the most prominent findings in mood disorders at postmortem, and the possibility of a mechanistic overlap between mood disorders and multiple sclerosis has been suggested previously (Mechawar and Savitz, 2016). This potential link raises the question of whether some of the new-generation biologics that target Th1/Th17 cells in multiple sclerosis could have therapeutic effects in BD. Also potentially consistent with the authors’ results, a small postmortem study reported an increase in CD3+ lymphocyte densities in the hippocampi of individuals with residual schizophrenia although the different T-cell subsets could not be differentiated in this analysis (Busse et al., 2012). Depending on feasibility, characterization of effector CD8+ cell density and localization at postmortem would be one way to extend the current work. The upstream cause of this putative CD8+ cell-mediated response is unclear. As Magioncalda et al. (2018) note, infectious agents and/or autoimmunity are one possibility. There are also parallels between Magioncalda et al’s disease model and preclinical work demonstrating that repeated exposure to psychological stress increases monocyte trafficking to the brain leading to neuroinflammation, dendritic remodeling, and the development of anxiety and depression-like behavior (Hodes et al., 2015). At least in vitro, Th1 and Th17 cells can potentiate microglial activation, shifting the balance towards an inflammatory M1-like phenotype (Gonzalez and Pacheco, 2014). Thus, modifying the cross-talk between microglia and T lymphocytes may constitute another point of therapeutic intervention. Nevertheless, the effect of T-cell trafficking to the brain may be complex, conceivably comprising an adaptive mechanism designed to terminate the inflammatory response. Collectively, several animal studies suggest that stress-induced changes in the adaptive immune system, unlike the innate immune system, protect against the deleterious effects of stress. For instance, maladaptive responses to psychological stress are more prominent in T-cell-deficient (Rag2−/−) mice than wild-type mice, an effect mediated by the protective effects of Tcells reactive to brain antigens such as myelin basic protein (Cohen et al., 2006). Similarly, lymphocytes from mice undergoing chronic social defeat stress that were adoptively transferred into Rag2(−/−) mice were shown to promote hippocampal neurogenesis and reduce inflammation and anxiety-like behavior (Brachman et al., 2015). Notably, these studies did not differentiate between the effects of a Th1 response, as observed by Magioncalda et al. (2018), and a Th2 response, which may have been responsible for the aforementioned